Structural plasticity of dendritic spines in the hippocampus is essential for learning and the endurance of long- term potentiation (LTP). However, in the mature brain, enhancement of synaptic strength at some synapses must be balanced by a weakening or elimination of other synapses to ensure that the total amount of excitatory input is not in constant flux along a dendritic segment. Recently, we found that 2 hours after the induction of LTP with naturalistic theta burst stimulation (TBS), there was a reduction in the number of small thin spines that was perfectly counterbalanced by an enlargement of PSDs on remaining spines, particularly those containing polyribosomes. The enlargement of PSDs was sufficient to ensure that the total amount of synaptic area supported by the dendrites remained constant following induction of LTP. This suggests that dendrites distribute limited resources such as polyribosomes to spines depending on their level of synaptic activity and raises the question of how the rearrangement of synaptic weight is mediated. We hypothesize that this local coordination is mediated in part by intracellular calcium stored and released from smooth endoplasmic reticulum (SER) that is present throughout the dendritic shaft but only in a subset of dendritic spines. SER is essential for regulation of cytoplasmic calcium during physiological levels of synaptic activation and is a major target of pathological states induced by both acute and chronic neurological disorders. Therefore, a better understanding of SER regulation with normal types of activity such as LTP is crucial to understanding pathological states of calcium regulation. We propose to quantify for the first time the structure and distribution of SER throughout dendrites and spines at 2 hr after the induction of TBS-LTP. We will also determine the role of calcium released from functionally distinct stores in coordinating structural synaptic plasticity along mature CA1 dendrites. PUBLIC HEALTH RELEVANCE: Structural plasticity of dendritic spines and their synapses underlies the storage of information throughout the brain. Many neurological disorders, including mental retardation and neurodegenerative diseases, are correlated with a distortion of spines and dendrites that interferes with the remodeling of synapses. Thus characterizing mechanisms of structural synaptic plasticity will help to identify therapeutic targets for when this process is disrupted. We hypothesize that coordination of structural synaptic plasticity in the hippocampus is mediated in part by intracellular calcium stored and released from smooth endoplasmic reticulum (SER) that is present throughout the dendritic shaft but only in a subset of dendritic spines. Under normal conditions, elevation in cytoplasmic calcium released from intracellular stores is transient and important for triggering multiple pathways involved in plasticity. However, during the progression of neurodegenerative diseases and even normal aging, the ability of neurons to regulate fluxes in calcium can become compromised. Thus SER is important for achieving a balance between enhanced synaptic efficacy observed with the acquisition of information and excitotoxic synaptic activation triggered by pathological states. This proposal will advance our understanding of the relationship between structural synaptic plasticity and regulation of intracellular calcium and perhaps will provide insight into developing treatments that will promote recovery from pathological states without compromising mechanisms of memory.